Data Supplement

• Data Supplement -

  Supplemental Figure 1 - Plots showing the SSR values for the optimized parameter sets with five different initial clusters of the CGNM.
  

  Supplemental Figure 2 - Plots showing a range of the optimized parameters for which the SSR values were less than 2.30 starting from five different initial clusters.
  

  Supplemental Figure 3 - The optimized results using the model without target binding.
  

  Supplemental Figure 4 - Fitted and observed blood bosentan concentrations after intravenous and oral administration without low-dose data (10 mg, or 10 and 50 mg).
  

  Supplemental Figure 5 - Temporal profiles of hepatic blood concentration after intravenous and oral administration of bosentan.
  

  Supplemental Table 1 - Clinical data used in this study.

  Supplemental Table 2 - List of fixed parameters in the bosentan PBPK model. 

  Supplemental Table 3 - Comparison of optimized parameter values with and without target binding for PBPK model (PBPK model with the five-compartment or one-compartment liver model).
  

  Supplemental Table 4 - Parameter values optimized without using the low-dose data.
  

  Supplemental Table 5- Reported information on bosentan to target molecules or tissues based on in vitro study.
  

  Supplemental Equations